Alectinib is an orally available inhibitor of the receptor tyrosine kinase anaplastic lymphoma kinase (ALK) with antineoplastic activity. Upon administration, alectinib binds to and inhibits ALK kinase, ALK fusion proteins as well as the gatekeeper mutation ALKL1196M known as one of the mechanisms of acquired resistance to small-molecule kinase inhibitors. The inhibition leads to the disruption of ALK-mediated signaling and eventually inhibits tumor cell growth in ALK-overexpressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development. ALK dysregulation and gene rearrangements are associated with a series of tumors.
Alectinib is a tyrosine kinase receptor inhibitor and antineoplastic agent used in the therapy of selected forms of advanced non-small cell lung cancer. Alectinib is associated with a moderate rate of transient elevations in serum aminotransferase levels during therapy and with rare instances of clinically apparent acute liver injury.
Alectinib hydrochloride is hydrochloride obtained by combining alectinib with one molar equivalent of hydrochloric acid. Used for the treatment of patients with anaplastic lymphoma kinase-positive, metastatic non-small cell lung cancer. It has a role as an antineoplastic agent and an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor. It contains an alectinib(1+).
Alectinib is an organic heterotetracyclic compound that is 6,6-dimethyl-5,6-dihydro-11H-benzo[b]carbazol-11-one carrying additional cyano, 4-(morpholine-4-yl)piperidines-1-yl and ethyl substituents at positions 3, 8 and 9 respectively. Used (as the hydrochloride salt) for the treatment of patients with anaplastic lymphoma kinase-positive, metastatic non-small cell lung cancer. It has a role as an EC 2.7.10.1 (receptor protein-tyrosine kinase) inhibitor and an antineoplastic agent. It is an organic heterotetracyclic compound, a member of morpholines, a member of piperidines, a nitrile, and an aromatic ketone. It is a conjugate base of an alectinib(1+).
Mechanism of Action
Alectinib is a second-generation oral drug that selectively inhibits the activity of anaplastic lymphoma kinase (ALK) tyrosine kinase. It is specifically used in the treatment of non-small cell lung cancer (NSCLC) expressing the ALK-EML4 (echinoderm microtubule-associated protein-like 4) fusion protein that causes the proliferation of NSCLC cells. Inhibition of ALK prevents phosphorylation and subsequent downstream activation of STAT3 and AKT resulting in reduced tumor cell viability. Both alectinib and its major active metabolite M4 demonstrate similar in vivo and in vitro activity against multiple mutant forms of ALK.
Alectinib is a tyrosine kinase receptor inhibitor and antineoplastic agent used in the therapy of selected forms of advanced non-small cell lung cancer. Alectinib is associated with a moderate rate of transient elevations in serum aminotransferase levels during therapy and with rare instances of clinically apparent acute liver injury.
Indications
- Alectinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
- Alecensa as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). Alecensa as monotherapy is indicated for the treatment of adult patients with ALK‑positive advanced NSCLC previously treated with crizotinib.,
Use in Cancer
Alectinib is approved to treat:
- Non-small cell lung cancer is ALK-positive and has metastasized (spread to other body parts).
Contraindications
The following conditions are contraindicated with this drug. Check with your physician if you have any of the following:
- a bacterial infection
- an infection due to a fungus
- opportunistic fungal infection
- an infection due to a protozoa organism
- spread of cancer to the brain or spinal cord
- untreated decreased level of thyroid hormones
- thyroid gland inflammation
- diabetes
- disease in which the body has an immune response against itself
- confusion
- toxic psychosis
- repeated seizures with unconsciousness between episodes
- myasthenia gravis, a skeletal muscle disorder
- method of removing waste/poison from blood with dialysis
- a heart attack
- angina, a type of chest pain
- bacterial infection of the heart valve
- pericardial tamponade, a disorder of the heart
- supraventricular tachycardia
- rapid ventricular heartbeat
- atrial fibrillation
- slow heartbeat
- abnormal heart rhythm
- capillary leak syndrome, a condition where fluid leaks out of small blood vessels
- low blood pressure
- fluid in the lungs
- lung failure causing loss of breath
- Crohn’s disease
- an ischemic bowel, a condition where the blood flow to the intestine is significantly decreased
- a hole in the intestine
- liver problems
- inflammation of the gallbladder
- bleeding of the stomach or intestines
- glomerulonephritis, a condition that affects the kidneys
- bullous pemphigoid
- scleroderma, hardening and tightening of the skin and connective tissues
- arthritis
- coma
- mental status changes
- seizures
- visible water retention
- decreased urine production
- a patient who is producing milk and breastfeeding
- decreased blood volume
- inflammation of blood vessels that carry blood in the brain
- sepsis
- chronic kidney disease stage 5 (failure)
- kidney disease with likely reduction in kidney function
Dosage
Strengths: 150 mg
Non-Small Cell Lung Cancer
- 600 mg orally 2 times a day with food until disease progression or unacceptable toxicity
Renal Dose Adjustments
- Mild (CrCl 60 to less than 90 mL/min) or moderate (30 to less than 60 mL/min renal impairment: No adjustment recommended.
- Severe renal impairment (CrCl less than 30 mL/min) or end-stage renal disease: Data not available
- Grade 3 renal impairment: Temporarily withhold therapy until recovery to baseline or to 1.5 x ULN or less, then resume at reduced dose.
- Grade 4 renal impairment: Permanently discontinue therapy.
Liver Dose Adjustments
- Mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic dysfunction: No adjustment recommended.
- Severe hepatic dysfunction (Child-Pugh C): Reduce dose to 450 mg orally 2 times a day.
- ALT or AST elevation of greater than 5 times the upper limit of normal (ULN) with total bilirubin 2 x ULN or less: Temporarily withhold therapy until recovery to baseline or to 3 x ULN or less, then resume at a reduced dose.
- ALT or AST elevation greater than 3 x ULN with total bilirubin elevation greater than 2 x ULN in the absence of cholestasis or hemolysis: Permanently discontinue therapy.
- Total bilirubin elevation greater than 3 x ULN: Temporarily withhold therapy until recovery to baseline or to 1.5 x ULN or less, then resume at a reduced dose.
Dose Adjustments
Dose Reduction Schedule for Adverse Reactions:
- Starting dose: 600 mg orally 2 times a day
- First Dose Reduction: 450 mg orally 2 times a day
- Second Dose Reduction: 300 mg orally 2 times a day twice a day
- Discontinue therapy if 300 mg orally 2 times a day is not tolerated.
BLOOD CREATINE PHOSPHOKINASE (CPK) ELEVATION:
- Greater than 5 x ULN: Temporarily withhold therapy until recovery to baseline or to 2.5 x ULN or less, then resume at the same dose.
- Greater than 10 x ULN or second occurrence of CPK elevation greater than 5 x ULN: Temporarily withhold therapy until recovery to baseline or to 2.5 x ULN or less, then resume at a reduced dose.
Side Effects
The Most Common
- The most common adverse reactions (>5%) associated with alectinib use were fatigue,
- constipation,
- edema, and myalgia.
- hepatotoxicity, interstitial lung disease (ILD)/pneumonitis,
- bradycardia,
- severe myalgia and
- creatine phosphokinase (CPK) elevation, and
- embryo-fetal toxicity.
- numbness or tingling in hands and feet
- signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
- signs of kidney problems (e.g., change in the amount or colour of urine, increased urination at night, blood in the urine, swelling in the feet or legs)
- signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
- signs of muscle damage (e.g., unexplained muscle pain, tenderness or weakness, or brown or discoloured urine)
- slowed heartbeat (e.g., dizziness, lightheadedness, fainting)
- vision changes (e.g., blurred vision, loss of sight, black dots or white spots in vision, seeing double)
More Common
- constipation
- diarrhea
- swelling in your hands, face, or eyelids
- headache
- weight gain
- rash
- new or worsening shortness of breath, difficulty breathing, or cough
- fever
- sudden chest pain
- dizziness, lightheadedness, or fainting
- vision changes
- sudden muscle pain, tenderness, or weakness
Rare
- back pain
- tiredness
- rash
- itchy skin
- loss of appetite
- nausea
- vomiting
- yellowing of skin or the whites of your eyes
- pain on the right side of your stomach area
- change in the amount or color of your urine
- new or worsening swelling in your legs or feet
- bleeding or bruising more easily than normal
Drug Interactions
There may be an interaction between alectinib and any of the following:
- alpha-agonists (e.g., clonidine, methyldopa)
- amiodarone
- beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
- ceritinib
- dabigatran
- digoxin
- diltiazem
- donepezil
- dronedarone
- fentanyl
- fingolimod
- flecainide
- galantamine
- grapefruit juice
- guanfacine
- lacosamide
- lanreotide
- methotrexate
- octreotide
- ozanimod
- pasireotide
- propafenone
- rivastigmine
- siponimod
- tizanidine
- tofacitinib
- verapamil
Drug-Food Interactions
- Exercise caution with grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of alectinib.
- Exercise caution with St. John’s Wort. This herb induces CYP3A metabolism, which may reduce serum levels of alectinib.
- Take it with food.
Pregnancy and Lactation
Pregnancy
This medication should not be used during pregnancy unless the benefits outweigh the risks. Women of childbearing age who are taking alectinib and women whose partners are taking alectinib should use an effective method of birth control, such as condoms, during treatment and for at least 3 months after stopping the medication. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
No information is available on the clinical use of alectinib during breastfeeding. Females of reproductive potential are advised to use effective contraception during treatment with alectinib and for 1 week following the final dose. Because alectinib is more than 99% bound to plasma proteins, the amount in milk is likely to be low. However, its half-life is about 33 hours and it might accumulate in the infant. The manufacturer recommends that breastfeeding be discontinued during alectinib therapy and for 1 week after the last dose.
What special precautions should I follow?
Before taking alectinib,
- tell your doctor and pharmacist if you are allergic to alectinib, any other medications, or any of the ingredients in alectinib capsules. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: medications to treat high blood pressure or heart problems. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you have or have ever had liver disease, lung or breathing problems, or a slow or irregular heartbeat.
- tell your doctor if you are pregnant or plan to become pregnant, or if you plan to father a child. You should not become pregnant while you are taking alectinib. If you are a female, you should use a reliable method of birth control while taking alectinib and for at least 1 week after your final dose. If you are a male, you and your female partner should use effective birth control while you are taking alectinib and for 3 months after your final dose. If you or your partner becomes pregnant while taking alectinib call your doctor immediately. Alectinib may harm the fetus.
- tell your doctor if you are breastfeeding. You should not breastfeed while taking alectinib and for 1 week after your last dose.
- plan to avoid unnecessary or prolonged exposure to sunlight (including sunlamps and tanning beds) and to wear protective clothing, sunglasses, and a sunscreen that has a sun protection factor (SPF) of at least 50 while taking alectinib and for at least 7 days after your last dose. Alectinib may make your skin sensitive to sunlight.
Are there any other Warnings for this medication?
Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breastfeeding, and any other significant facts about your health. These factors may affect how you should use this medication.
Drowsiness/reduced alertness: Alectinib may cause drowsiness, dizziness, or vision changes, affecting your ability to drive or operate machinery. Avoid driving, operating machinery, or performing other potentially hazardous tasks until you have determined how this medication affects you.
Heart disease: Alectinib can cause a very low heart rate. If you have heart conditions with low heart rate such as certain types of arrhythmias, congestive heart failure, sick sinus syndrome, or certain types of heart block, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
If you experience signs of a slow heartbeat, such as dizziness, lightheadedness, and fainting, let your doctor know as soon as possible.
Gastrointestinal perforation: Rarely, do people taking alectinib experience a gastrointestinal perforation. This is a condition where a hole forms through the walls of the digestive tract and is a medical emergency. If you have risk factors for this type of complication, such as a history of diverticulitis, cancer that has spread to the digestive tract, or are taking other medications that may cause gastrointestinal perforation, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.
Grapefruit juice: Grapefruit juice, grapefruit, starfruit, pomegranate, and Seville oranges can interfere with how this medication is broken down and removed from the body. Consuming any of these products while taking alectinib may cause the medication to build up in the body, causing severe side effects. For this reason, it is advisable to avoid these fruits and their juices while taking this medication.
Kidney function: Alectinib may cause decreased kidney function. If you experience signs of kidney problems, such as a change in the amount or color of urine, increased urination at night, blood in the urine, or swelling in the feet or legs, contact your doctor.
Liver function: Liver disease or reduced liver function may cause this medication to build up in the body, causing side effects. If you have liver problems, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed. Your doctor may want to test your liver function regularly with blood tests while you are taking this medication.
Alectinib may also cause harm to the liver. If you experience symptoms of liver problems such as fatigue, feeling unwell, loss of appetite, nausea, yellowing of the skin or whites of the eyes, dark urine, pale stools, abdominal pain or swelling, and itchy skin, contact your doctor immediately.
Lung inflammation: Rarely, some people taking alectinib have experienced lung inflammation (interstitial lung disease), causing difficulty breathing. This complication can be serious and sometimes fatal. If you experience new or worsening shortness of breath or cough (with or without fever) at any time while you are taking alectinib, contact your doctor immediately.
Muscle effects: Muscle damage has been associated with the use of alectinib. Report any unexplained muscle pain, tenderness, weakness or cramps, or any brown or discolored urine to your doctor immediately, particularly if you are also experiencing malaise (a general feeling of being unwell) or fever.
Sensitivity to sunlight: This medication may increase the sensitivity of the skin to sunlight, increasing the risk of sunburn. Avoid exposure to sunlight for long periods of time, particularly between the hours of 10 am and 2 pm, while you are taking this medication and for 7 days after completing treatment. Wear broad-spectrum sunscreen and lip balm with an SPF of 50 or higher. If you notice any unusual skin rash or peeling, contact your doctor immediately.
Breast-feeding: It is not known if alectinib passes into breast milk. If you are a breastfeeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding.
Children: The safety and effectiveness of using this medication have not been established for children.
Seniors: People over the age of 75 are more likely to experience severe side effects of taking alectinib.
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